This invention relates to novel isoxazolines which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A2 synthetase inhibitors or receptor antagonists, which act against thromboxane A2; and hirudin, which acts against thrombin. Additionally, current antiplatelet drugs effective against platelet glycoprotein IIb/IIIa complex include Reopro(trademark), Integrilin(trademark), and Aggrastat(trademark).
A common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.
GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
In addition to GPIIb/IIIa, increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell-cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane glycoproteins containing xcex1- and xcex2-subunits. Integrin subfamilies contain a common xcex2-subunit combined with different xcex1-subunits to form adhesion receptors with unique specificity. The genes for eight distinct xcex2-subunits have been cloned and sequenced to date.
Two members of the xcex21 subfamily, xcex14/xcex21 and xcex15/xcex21 have been implicated in various inflammatory processes. Antibodies to xcex14 prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther-Janssen et al., J. Immunol., 1991, 147:4207). Additional studies with monoclonal anti-xcex14 antibodies provide evidence that xcex14/xcex21 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553; Yednock et al., Nature, 1992, 356:63). Anti-xcex14 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).
The xcex1v/xcex23 heterodimer, commonly referred to as the vitronectin receptor, is another member of the xcex23 integrin subfamily and has been described in platelets, endothelial cells, melanoma, smooth muscle cells and on the surface of osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence. Possible roles for xcex1v/xcex23 in angiogenesis, tumor progression, and neovascularization have been proposed (Brooks et al., Science, 1994, 264:569-571). A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the xcex1v/xcex23 receptor in this process and suggest that a selective xcex1v/xcex23 antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).
Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi. See European Patent Application Publication Number 478363, European Patent Application Publication Number 478328, and PCT Patent Application 9307867, and European Patent Application Publication Number 4512831.
U.S. Pat. No. 5,607,952, published Mar. 4, 1997, discloses fibrinogen receptor antagonists, wherein the substituted 4-phenylthiazole containing compounds of general formula: 
are disclosed.
Canadian Patent Application 2,122,571, published Nov. 11, 1994, discloses fibrinogen receptor antagonists, wherein compounds of general formula:

are disclosed.
Copending commonly assigned U.S. patent application U.S. Ser. No. 08/337,920, filed Nov. 10, 1994, Wityak et al.(PCT WO95/14683, published Jun. 1, 1995) discloses compounds having the general formula: 
which are useful as IIB/IIIA antagonists. See also related PCT WO96/38426, published Dec. 5, 1996.
Commonly assigned U.S. Pat. No. 5,446,056, issued Aug. 29, 1995, discloses compounds having the general formula: 
which are useful as IIB/IIIA antagonists. See also PCT WO96/38426, published Dec. 5, 1996.
Commonly assigned U.S. Pat. No. 5,710,159, issued Jan. 20, 1998, discloses compounds having the general formula: 
which are useful as avb3 antagonists.
None of the above references teach or suggest the compounds of the present invention which are described in detail below.
The present invention provides novel nonpeptide compounds which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes. The compounds of the present invention are useful for the treatment of thrombosis, inflammation, bone degradation, tumors, metastases, and cell aggregation-related conditions in a mammal.
One aspect of this invention provides novel compounds of Formula (I) (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula (I), and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
The present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula (I) alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase, streptokinase, or reteplase; or combinations thereof.
The present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula (I), for the treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.
The present invention provides novel nonpeptide compounds of Formula (I) (described below) which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes. The compounds of the present invention are useful for the treatment of thrombosis, inflammation, bone degradation, tumors, metastases, and cell aggregation-related conditions in a mammal.
One aspect of this invention provides compounds of Formula (I) (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to the platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula (I), and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
[1] This invention relates to novel compounds of the Formula (I): 
or a pharmaceutically acceptable salt or prodrug form thereof, wherein:
R1 is selected from
R2a(R3)Nxe2x80x94Vxe2x80x94,
R2a(R3)N(CH2)qxe2x80x94,
R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94,
R2(R2b)N(R3Nxe2x95x90)C(CH2)qxe2x80x94,
R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94,
R2(R11O)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94,
R2(R2b)N(R11ONxe2x95x90)Cxe2x80x94Vxe2x80x94, 
V is selected from:
xe2x80x94(C1-C4 alkyl)-,
xe2x80x94(C2-C4 alkenyl)-,
xe2x80x94(C2-C4 alkynyl)-,
xe2x80x94(phenyl)-, said phenyl substituted with 0-2 groups independently selected from R9,
xe2x80x94(pyridyl)xe2x80x94, said pyridyl substituted with 0-2 groups independently selected from R9, or
xe2x80x94(pyridazinyl)xe2x80x94, said pyridazinyl substituted with 0-2 groups independently selected from R9;
Z is selected from: a bond, O, S, S(xe2x95x90O), and S(xe2x95x90O)2;
R2a is R2 or R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94;
R2, R2b, and R3 are independently selected from:
H,
C1-C10 alkyl,
C3-C6 alkenyl,
C3-C6 alkynyl,
C3-C10 cycloalkyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
C2-C7 alkylcarbonyl,
C1-C4 haloalkyl,
aryl,
arylcarbonyl,
aryl(C1-C4 alkyl)-,
benzhydryl,
benzhydryl (C1-C4 alkyl)-,
heteroaryl,
heteroaryl(C1-C5 alkyl)-, and
a cleavable protecting group selected from:
C1-C6 alkoxycarbonyl,
C3-C11 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl,
aryloxycarbonyl,
aryl (C1-C10 alkoxy)carbonyl,
(C1-C6 alkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
(C3-C11 cycloalkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
wherein at least one of R2, R2b, and R3 is H or a cleavable protecting group;
wherein said aryl groups of R2, R2b, and R3 may be substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, xe2x80x94CN, xe2x80x94SO2(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and
said heteroaryl groups of R2, R2b, and R3 may be substituted with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SO2CH3, and xe2x80x94NR21R22;
alternatively, R2 and R2b can be taken together with the nitrogen atom to which they are attached to form a 5-10 membered heterocyclic ring optionally containing one additional heteroatom selected from: N, O, or S; said heterocyclic ring being monocyclic or bicyclic; said heterocyclic ring being substituted with 0-2 R4;
R4, when a substituent on carbon, is independently selected from:
H, C1-C4 alkyl, aryl, and aryl(C1-C6 alkyl)-, wherein said aryl groups may be optionally substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl;
alternatively, when two R4 groups are attached to adjacent carbon atoms, they may be taken together with the atoms to which they are attached to form a fused 5-7 membered saturated, unsaturated or aromatic carbocyclic ring;
alternatively, when R4 is attached to a saturated carbon atom, it may also be xe2x95x90O or xe2x95x90S;
R4 when a substituent on nitrogen, is independently selected from:
H,
C1-C6 alkyl,
C3-C6 alkenyl,
C1-C10 alkoxycarbonyl,
C1-C10 alkylcarbonyl,
C1-C10 alkylsulfonyl,
C3-C10 cycloalkyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
C3-C11 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl,
aryl,
aryl (C1-C10 alkyl)-,
benzhydryl,
benzhydryl (C1-C4 alkyl)-,
arylcarbonyl,
aryloxycarbonyl,
arylsulfonyl,
aryl(C1-C10 alkyl) sulfonyl,
aryl(C2-C10 alkenyl)sulfonyl,
aryl(C1-C10 alkoxy) carbonyl,
heteroaryl,
heteroarylsulfonyl,
heteroarylcarbonyl,
heteroaryl(C1-C10 alkyl)-, and
heteroaryl(C1-C10 alkyl)carbonyl,
wherein said aryl or heteroaryl groups may be additionally substitututed with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SCH3, SOCH3, SO2CH3, or xe2x80x94NR21R22;
R4 when a substituent on sulfur, may be xe2x95x90O;
X is xe2x80x94CH2CH(Wa)xe2x80x94, xe2x80x94CH(Wa)CH2xe2x80x94, xe2x80x94CH(Wa)xe2x80x94, xe2x80x94OCH(Wb)xe2x80x94, xe2x80x94SCH(Wb)xe2x80x94, xe2x80x94NHCH(Wb)xe2x80x94, xe2x80x94OCH(Wb)CH2xe2x80x94, xe2x80x94SCH(Wb)CH2xe2x80x94, xe2x80x94NHCH(Wb)CH2xe2x80x94, xe2x80x94OCH2CH(Wa)xe2x80x94, xe2x80x94SCH2CH(Wa)xe2x80x94, or xe2x80x94NHCH2CH(Wa)-;
Y is selected from hydroxy,
C1-C10 alkyloxy,
C3-C11 cycloalkyloxy,
C6-C10 aryloxy,
C7-C11 arylalkyloxy,
C2-C10 alkylcarbonyloxyalkyloxy,
C2-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
C4-C10 cycloalkylcarbonyloxyalkyloxy,
C4-C10 cycloalkoxycarbonyloxyalkyloxy,
C4-C10 cycloalkoxycarbonylalkyloxy,
C7-C11 aryloxycarbonylalkyloxy,
C7-C12 aryloxycarbonyloxyalkyloxy,
C7-C12 arylcarbonyloxyalkyloxy,
C4-C10 alkoxyalkylcarbonyloxyalkyloxy,
(5-(C1-C4 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R28) (R29)Nxe2x80x94(C1-C10 alkoxy)-;
Wa is selected from:
H,
hydroxy,
xe2x80x94NR16R20,
xe2x80x94NR25R26,
C1-C10 alkoxy,
C1-C10 alkyl substituted with 0-3 R8, and
aryl substituted with 0-3 R8,
Wb is selected from:
H,
CH2OH,
CH2OR12,
CH2CO2R12,
CH2C(xe2x95x90O) NHR18,
CH2NR16R20,
CH2NR25R26,
C1-C8 alkyl substituted with 0-2 R8,
C3-C6 alkenyl,
C3-C10 cycloalkyl,
C4-C11 cycloalkylmethyl,
heteroaryl,
heteroaryl(C1-C6 alkyl),
aryl substituted with 0-3 R8, and
aryl(C1-C6 alkyl), said aryl substituted with 0-3 R8;
R5 is selected from:
H,
fluoro,
C1-C8 alkyl substituted with 0-2 R8,
C3-C6 alkenyl,
C4-C11 cycloalkylmethyl, and
aryl(C1-C6 alkyl)-;
R6 is H, methyl, or fluoro;
R7 is selected from:
H,
hydroxy,
C1-C4 alkoxy,
xe2x80x94C(xe2x95x90O)NHR18, and
xe2x80x94NR16R20;
R7a and R7b are independently selected from H, hydroxy, cyano, fluoro, methyl, and ethyl;
alternatively, when R7 and R7a occur on adjacent carbons R7 and R7a may be taken together to form a carbon-carbon double bond;
alternatively, when R7a and R7b occur on adjacent carbons R7a and R7b may be taken together to form a six carbon aromatic ring;
R8 is selected from:
H,
hydroxy,
cyano,
xe2x80x94CO2R12,
xe2x80x94C(xe2x95x90O)R13,
xe2x80x94OC(xe2x95x90O)R13,
xe2x80x94OC(xe2x95x90O)OR14,
xe2x80x94OR12,
xe2x80x94OCH2CO2R12,
xe2x80x94CO2CH2CO2R12,
xe2x80x94OC(xe2x95x90O)NR23R24,
xe2x80x94C(xe2x95x90O)NR23R24,
xe2x80x94NR25R26,
xe2x80x94NR27C(xe2x95x90O) R13,
xe2x80x94NR27C(xe2x95x90O) OR14,
xe2x80x94NR27SO2R14,
xe2x80x94SR14,
xe2x80x94SOR14,
xe2x80x94SO2R14,
xe2x80x94SO2NR23R24,
C1-C10 alkoxy,
C1-C10 alkylcarbonyl,
C2-C6 alkenyl,
C3-C10 cycloalkyl,
C4-C11 cycloalkylmethyl,
aryl, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, CO2R12, SO2Me, SOMe, SMe, or xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2;
R9 is selected from H, halogen, CF3, CN, C1-C4 alkyl, or C1-C4 alkoxy;
R10 is selected from:
H,
hydroxy,
CN,
carboxy,
xe2x80x94NR25R26;
C1-C6 alkyl,
C2-C6 alkenyl,
C2-C6 alkynyl,
C3-C7 cycloalkyl,
C7-C14 bicycloalkyl,
C1-C6 alkoxy,
C1-C6 alkylthio,
C1-C6 alkylsulfinyl,
C1-C6 alkylsulfonyl,
C1-C6 alkylcarbonyl,
C1-C6 alkoxycarbonyl,
aryl,
piperidinyl,
morpholinyl, and
pyridinyl;
R11 is selected from:
H,
C1-C8 alkyl,
C3-C6 alkenyl,
C3-C11 cycloalkyl,
C4-C11 cycloalkylmethyl,
aryl,
aryl(C1-C4 alkyl)-, and
C1-C10 alkyl substituted with 1-2 R10;
R12 is selected from:
H,
C1-C8 alkyl,
C3-C6 alkenyl,
C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl,
aryl,
aryl(C1-C4 alkyl)-, and
C1-C10 alkyl substituted with 1-2 R10;
R13 is selected from:
hydrogen,
C1-C8 alkyl,
C3-C6 alkenyl,
C3-C11 cycloalkyl,
C4-C11 cycloalkylmethyl,
aryl,
aryl(C1-C4 alkyl)-,
heteroaryl,
heteroaryl(Cl-C4 alkyl)-, and
C1-C10 alkyl substituted with 1-2 R10;
R14 is selected from:
C1-C8 alkyl,
C2-C6 alkenyl,
C3-C11 cycloalkyl,
C4-C11 cycloalkylmethyl,
aryl,
aryl(C1-C4 alkyl)-, and
C1-C10 alkyl substituted with 1-2 R10;
R15 is selected from:
H,
OH,
xe2x80x94OR12,
xe2x80x94CO2R12,
xe2x80x94C(xe2x95x90O)NR23R24,
xe2x80x94OC(xe2x95x90O) NR23R24,
C1-C10 alkoxycarbonyl substituted with 0-2 R8;
C1-C10 alkyl substituted with 0-3 R8;
C2-C10 alkenyl substituted with 0-3 R8; and
C1-C10 alkoxy substituted with 0-3 R8;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR17,
xe2x80x94C(xe2x95x90O) R18,
xe2x80x94C(xe2x95x90O)NR17R18,
xe2x80x94C(xe2x95x90O)NHSO2R17,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R17,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR17,
xe2x80x94C(xe2x95x90O)NHSO2NHR17,
xe2x80x94SO2R17,
xe2x80x94SO2NR17R18, and
xe2x80x94SO2NHC(xe2x95x90O) OR17;
R17 is selected from:
C1-C8 alkyl substituted with 0-2 R19,
C3-C8 alkenyl substituted with 0-2 R19,
C3-C8 alkynyl substituted with 0-2 R19,
C3-C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19, aryl(C1-C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19;
R18 is selected from H or R17;
R19 is selected from:
H,
halogen,
CF3,
CN,
NO2,
NR25R26,
C1-C8 alkyl,
C2-C6 alkenyl,
C2-C6 alkynyl,
C3-C11 cycloalkyl,
C3-C11 cycloalkyl(C1-C4 alkyl)-,
aryl,
aryl(C1-C6 alkyl)-,
C1-C6 alkoxy, and
C1-C4 alkoxycarbonyl;
R20 is selected from:
H,
C1-C10 alkyl,
C2-C6 alkenyl,
C3-C11 cycloalkyl,
C3-C11 cycloalkyl (C1-C4 alkyl)-,
aryl, and
aryl(C1-C10 alkyl)xe2x80x94;
R21 and R22 are each independently H, methyl, ethyl, propyl, or butyl;
R23 is selected from:
hydrogen,
C1-C8 alkyl,
C3-C6 alkenyl,
C3-C11 cycloalkyl,
C4-C11 cycloalkylmethyl,
hydroxy,
C1-C6 alkoxy,
benzyloxy,
aryl,
aryl(C1-C4 alkyl)-,
heteroaryl,
heteroaryl(C1-C4 alkyl)-,
adamantylmethyl, and
C1-C10 alkyl substituted with 1-2 R10;
R24 is selected from:
C1-C8 alkyl,
C2-C6 alkenyl,
C3-C11 cycloalkyl,
C4-C11 cycloalkylmethyl,
aryl,
aryl(C1-C4 alkyl)-, and
C1-C10 alkyl substituted with 1-2 R10;
R25 and R26 are, independently, selected from:
H,
C1-C10 alkyl,
C1-C10 alkoxycarbonyl,
C1-C10 alkylcarbonyl,
C1-C10 alkylsulfonyl,
aryl,
aryl(C1-C4 alkyl)-,
arylcarbonyl,
aryloxycarbonyl,
arylsulfonyl,
aryl(C1-C10 alkoxy)carbonyl,
aryl(C1-C10 alkyl)sulfonyl,
aryl(C2-C10 alkenyl)sulfonyl,
C2-C6 alkenyl,
C3-C10 cycloalkyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
C3-C10 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl,
heteroaryl,
heteroarylcarbonyl,
heteroarylsulfonyl, and
heteroaryl(C1-C4 alkyl)carbonyl,
wherein said aryl groups are optionally substituted with 1-3 substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2;
R27 is selected from H, methyl, ethyl, propyl, butyl, benzyl, phenethyl, cyclopropyl, and cyclopropylmethyl;
R28 and R29 are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl, (C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br , CF3, and NO2;
n is 0 or 1;
q is 1, 2, 3, or 4;
r is 0, 1, or 2; and
s is 1, 2, 3, or 4.
[2] Preferred compounds of this first embodiment are those of Formula (Ia) wherein:
R1 is selected from
R2a(R3)Nxe2x80x94Vxe2x80x94, R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94, R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94, R2(R11O)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94, R2(R2b)N(R11ONxe2x95x90)Cxe2x80x94Vxe2x80x94, 
V is selected from:
xe2x80x94(C1-C4 alkyl)-,
xe2x80x94(phenyl)-, said phenyl substituted with 0-2 groups independently selected from R9,
xe2x80x94(pyridyl)-, said pyridyl substituted with 0-2 groups independently selected from R9, or
xe2x80x94(pyridazinyl)-, said pyridazinyl substituted with 0-2 groups independently selected from R9;
Z is selected from: a bond, O, and S(xe2x95x90O)2;
X is xe2x80x94CH2CH(Wa)xe2x80x94, xe2x80x94CH(Wa)CH2xe2x80x94, xe2x80x94CH(Wa)xe2x80x94, xe2x80x94OCH(Wb)xe2x80x94, xe2x80x94SCH(Wb)xe2x80x94, xe2x80x94NHCH(Wb)xe2x80x94, or xe2x80x94OCH(Wb)CH2xe2x80x94;
Wa is selected from:
H, hydroxy, xe2x80x94NHR16, xe2x80x94NR25R26, C1-C10 alkoxy, C1-C10 alkyl substituted with 0-3 R8, and aryl substituted with 0-3 R8,
R6 is H;
R7 is selected from:
H, hydroxy, methoxy, ethoxy, propoxy, butoxy, xe2x80x94C(xe2x95x90O)NHR18, and xe2x80x94NR16R20;
R12 is selected from H, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
R15 is selected from H, OH, xe2x80x94OR12, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)NR23R24, and xe2x80x94OC(xe2x95x90O) NR23R24;
R16 is selected from xe2x80x94C(xe2x95x90O)OR17, xe2x80x94C(xe2x95x90O)R18, xe2x80x94SO2R17, and xe2x80x94SO2NR17R18;
R17 is selected from:
C1-C8 alkyl substituted with 0-2 R19,
C3-C8 alkenyl substituted with 0-2 R19,
C3-C8 alkynyl substituted with 0-2 R19,
C3-C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1-C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, said heterocyclic ring being substituted with 0-4 R19, said heterocyclic ring being substituted with 0-4 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring being substituted with 0-4 R19;
R18 is selected from H or C1-C5 alkyl;
n is 0 or 1;
q is 1, 2, 3, or 4;
r is 0, 1, or 2; and
s is 1, 2, 3, or 4.
[3] More preferred compounds of this first embodiment are those of Formula (Ia) 
wherein:
R1 is selected from R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94, R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94, 
V is selected from:
xe2x80x94(C1-C4 alkyl)-,
xe2x80x94(pyridyl)-, and
xe2x80x94(phenyl)-, said phenyl substituted with 0-2 groups independently selected from F, Br, methyl, and methoxy;
Z is a bond or O;
R2, R2b, and R3 are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C4 alkyl)-, C2-C7 alkylcarbonyl, C1-C4 haloalkyl, aryl, arylcarbonyl, aryl(C1-C4 alkyl)-, benzhydryl, benzhydryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, and
a cleavable protecting group selected from:
C1-C6 alkoxycarbonyl,
C3-C cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl,
aryloxycarbonyl,
aryl(C1-C8 alkoxy) carbonyl,
(C1-C6 alkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
(C3-C8 cycloalkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
wherein at least one of R2, R2b, and R3 is H or a cleavable protecting group;
wherein said aryl groups of R2, R2b, and R3 may be substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, xe2x80x94CN, xe2x80x94SO2(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and
said heteroaryl groups of R2, R2b, and R3 may be substituted with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SO2CH3, and xe2x80x94NR21R22;
alternatively, R2 and R2b can be taken together with the nitrogen atom to which they are attached to form a 5-10 membered heterocyclic ring system selected from morpholine, piperidine, piperazine, pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine, 1,4-benzoxazine, 8-oxo-3-aza-bicyclo[3.2.1]octane, 1,4-dioxa-8-azaspiro[4.5]decane, or azepine, said heterocyclic ring being substituted with 0-2 R4;
X is xe2x80x94CH2CH(Wa)xe2x80x94, xe2x80x94CH(Wa)CH2xe2x80x94, xe2x80x94CH(Wa)xe2x80x94, or xe2x80x94OCH(Wb)xe2x80x94;
Y is selected from hydroxy,
C1-C6 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
Wa is H or xe2x80x94NHR16;
Wb is H, methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, pyridylethyl, (indol-3-yl)ethyl, CH2C(xe2x95x90O)NHR18, and CH2NHR16;
R8 is selected from:
H, hydroxy, cyano, xe2x80x94Co2R12, xe2x80x94C(xe2x95x90O)R13, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR25R26, xe2x80x94SR14, xe2x80x94SOR14, xe2x80x94SO2R14, C1-C10 alkoxy, C1-C10 alkylcarbonyl,
aryl, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;
R15 is selected from H, OH, xe2x80x94OR12, and xe2x80x94OC(xe2x95x90O)NR23R24;
R16 is xe2x80x94C(xe2x95x90O)OR17 or xe2x80x94SO2R17;
R17 is selected from:
C1-C8 alkyl,
C2-C8 alkenyl,
aryl substituted with 0-4 R19,
aryl(C1-C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, said heterocyclic ring being substituted with 0-4 R19, said heterocyclic ring being substituted with 0-4 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring being substituted with 0-4 R19;
R19 is selected from H, halogen, CF3, CN, NO2, NR25R26, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C3-C11 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C1-C4 alkoxycarbonyl;
n is 0 or 1;
q is 1, 2, 3, or 4;
r is 0, 1, or 2; and
s is 1, 2, 3, or 4.
[4] Even more preferred compounds of this first embodiment are compounds of Formula (Ia) wherein:
R1 is R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94 or R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94;
V is -(pyridyl)- or -(phenyl)-, said phenyl substituted with 0-2 groups independently selected from F, Br, methyl, and methoxy;
Z is a bond or O;
R2, R2b, and R3 are independently selected from:
H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C4 alkyl)-, C2-C7 alkylcarbonyl, C1-C4 haloalkyl, arylcarbonyl, aryl(C1-C4 alkyl)-, benzhydryl, heteroaryl, heteroaryl(C1-C4 alkyl)-, and
a cleavable protecting group selected from:
C1-C4 alkoxycarbonyl,
C3-C6 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl,
aryl(C1-C8 alkoxy)carbonyl,
(C1-C6 alkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
(C3-C8 cycloalkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
wherein at least one of R2, R2b, and R3 is H or a cleavable protecting group;
wherein said aryl groups of R2, R2b, and R3 may be substituted with 0-3 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CF3, xe2x80x94CN, xe2x80x94SO2(CH3), xe2x80x94SO2(C2H5), xe2x80x94SO2 (C3H7), xe2x80x94SO2 (C4H9), xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and
said heteroaryl groups of R2, R2b, and R3 may be substituted with 0-2 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CF3, SO2CH3, and xe2x80x94NR21R22;
alternatively, R2 and R2b can be taken together with the nitrogen atom to which they are attached to form a 5-10 membered heterocyclic ring system selected from morpholine, piperidine, piperazine, pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine, 1,4-benzoxazine, 8-oxo-3-aza-bicyclo[3.2.1]octane, 1,4-dioxa-8-azaspiro[4.5]decane, or azepine, said heterocyclic ring being substituted with 0-2 R4;
R4, when a substituent on carbon, is independently selected from H, methyl, ethyl, propyl, butyl, and phenyl; wherein said phenyl groups may be optionally substituted with 0-3 groups selected from hydroxy, halogen, methoxy, methyl, ethyl, CF3, SCH3, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, methylenedioxydiyl, and ethylenedioxydiyl;
alternatively, when two R4 groups are attached to adjacent carbon atoms, they may be taken together with the atoms to which they are attached to form a fused 5-7 membered saturated, unsaturated or aromatic carbocyclic ring;
alternatively, when R4 is attached to a saturated carbon atom, it may also be xe2x95x90O or xe2x95x90S;
R4 when a substituent on nitrogen, is independently selected from H, methyl, ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, phenyl, phenylmethyl, phenylethyl, pyridyl, pyridylmethyl
wherein said phenyl or pyridyl groups may be additionally substitututed with 0-2 groups selected from hydroxy, halogen, methoxy, methyl, ethyl, CF3, SCH3, xe2x80x94NH2, xe2x80x94NH(CH3), and xe2x80x94N(CH3)2;
R4 when a substituent on sulfur, may be xe2x95x90O;
X is xe2x80x94CH2CH(Wa)xe2x80x94, xe2x80x94CH(Wa)xe2x80x94, or xe2x80x94OCH(Wb)xe2x80x94;
Y is selected from hydroxy; methoxy; ethoxy; isopropoxy; n-butyloxy; isobutyloxy; t-butoxy; benzyloxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
Wa is H or xe2x80x94NHR16;
Wb is H, methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, pyridylethyl, (indol-3-yl)ethyl, CH2C(xe2x95x90O)NHR18, and CH2NHR16;
R8 is selected from:
H, hydroxy, cyano, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)R13, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR25R26, xe2x80x94SR14, xe2x80x94SOR14, xe2x80x94SO2R14, C1-C4 alkoxy, C1-C4 alkylcarbonyl,
aryl, wherein said aryl is substituted with 0-3 groups selected from halogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;
R15 is H;
R16 is xe2x80x94SO2R17, xe2x80x94C(xe2x95x90O)OCH2CH2CH2CH3, xe2x80x94C(xe2x95x90O)OCH2CH(CH3)2 or xe2x80x94C(xe2x95x90O)OCH2(C6H5);
R17 is selected from:
C1-C8 alkyl,
aryl substituted with 0-2 R19,
aryl(C1-C6 alkyl)-substituted with 0-2 R19,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, said heterocyclic ring being substituted with 0-2 R19 said heterocyclic ring being substituted with 0-2 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring being substituted with 0-2 R19;
R19 is selected from:
H, halogen, CF3, CN, NO2, NR25R26, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C4 alkyl)-, C1-C4 alkoxy, and C1-C4 alkoxycarbonyl;
n is 1; and
s is 1 or 2.
[5] Specifically preferred compounds of this first embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
[[1-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(phenylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(n-propylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(ethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(piperidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(thiazolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(4-phenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(pyrrolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(2,6-dimethylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(2-fluorophenyl)piperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(2-methylphenyl)piperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(thiomorpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(4-propylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]acetic acid;
[[1-[3-[4-[(1,2,3,4-tetrahydro-2,7-naphthyridino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]oxy]-acetic acid;
[1-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(phenylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(n-propylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(ethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(piperidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(thiazolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(4-phenylpiperazino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(pyrrolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(2,6-dimethylpiperazino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(2-fluorophenyl)piperazino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(2-methylphenyl)piperazino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(thiomorpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(4-propylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid;
[1-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]acetic acid; and
[1-[3-[4-[(1,2,3,4-tetrahydro-2,7-naphthyridino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperidinyl]-acetic acid.
[8] A second embodiment of this invention provides a compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug form thereof wherein:
R1 is selected from
R2a(R3)Nxe2x80x94Vxe2x80x94,
R2a(R3)N(CH2)qxe2x80x94,
R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94,
R2(R2b)N(R3Nxe2x95x90)C(CH2)qxe2x80x94,
R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94,
R2(R11O)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94,
R2(R2b)N(R11ONxe2x95x90)Cxe2x80x94Vxe2x80x94, 
V is selected from:
xe2x80x94(C1-C4 alkyl)-,
xe2x80x94(C2-C4 alkenyl)-,
xe2x80x94(C2-C4 alkynyl)-,
xe2x80x94(phenyl)-, said phenyl substituted with 0-2 groups independently selected from R9,
xe2x80x94(pyridyl)-, said pyridyl substituted with 0-2 groups independently selected from R9, or
xe2x80x94(pyridazinyl)-, said pyridazinyl substituted with 0-2 groups independently selected from R9;
Z is selected from: a bond, O, S, S(xe2x95x90O), and S(xe2x95x90O)2;
R2a is R2 or R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94;
R2, R2b, and R3 are independently selected from:
H, C1-C10 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C4 alkyl)-, C2-C7 alkylcarbonyl, C1-C4 haloalkyl, aryl, arylcarbonyl, aryl(C1-C4 alkyl)-, benzhydryl, benzhydryl (C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C5 alkyl)-, and
a cleavable protecting group selected from:
C1-C6 alkoxycarbonyl,
C3-C11 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy) carbonyl,
(C1-C6 alkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
(C3-C11 cycloalkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
wherein at least one of R2, R2b, and R3 is H or a cleavable protecting group;
wherein said aryl groups of R2, R2b, and R3 may be substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, xe2x80x94CN, xe2x80x94SO2(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and
said heteroaryl groups of R2, R2b, and R3 may be substituted with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SO2CH3, and xe2x80x94NR21R22;
alternatively, R2 and R2b can be taken together with the nitrogen atom to which they are attached to form a 5-10 membered heterocyclic ring optionally containing one additional heteroatom selected from: N, O, or S; said heterocyclic ring being monocyclic or bicyclic; said heterocyclic ring being substituted with 0-2 R4;
R4, when a substituent on carbon, is independently selected from:
H, C1-C4 alkyl, aryl, and aryl(C1-C6 alkyl)-, wherein said aryl groups may be optionally substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl;
alternatively, when two R4 groups are attached to adjacent carbon atoms, they may be taken together with the atoms to which they are attached to form a fused 5-7 membered saturated, unsaturated or aromatic carbocyclic ring;
alternatively, when R4 is attached to a saturated carbon atom, it may also be xe2x95x90O or xe2x95x90S;
R4 when a substituent on nitrogen, is independently selected from:
H, C1-C6 alkyl, C3-C6 alkenyl, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl (C1-C4 alkyl)-, C3-C11 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, aryl, aryl(C1-C10 alkyl)-, benzhydryl, benzhydryl (C1-C4 alkyl)-, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, aryl(C1-C10 alkyl)sulfonyl, aryl(C2-C10 alkenyl)sulfonyl, aryl(C1-C10 alkoxy)carbonyl, heteroaryl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryl(C1-C10 alkyl)-, and heteroaryl(C1-C10 alkyl)carbonyl,
wherein said aryl or heteroaryl groups may be additionally substitututed with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SCH3, SOCH3, SO2CH3, or xe2x80x94NR21R22;
R4 when a substituent on sulfur, may be xe2x95x90O;
X is xe2x80x94OCH2CH(Wa)xe2x80x94, xe2x80x94SCH2CH(Wa)xe2x80x94, xe2x80x94NHCH2CH(Wa)xe2x80x94, xe2x80x94OCH(Wb)xe2x80x94, xe2x80x94SCH(Wb)xe2x80x94, xe2x80x94NHCH(Wb)xe2x80x94, xe2x80x94OCH(Wb)CH2xe2x80x94, xe2x80x94SCH(Wb)CH2xe2x80x94, or xe2x80x94NHCH(Wb)CH2xe2x80x94;
Y is selected from hydroxy,
C1-C10 alkyloxy,
C3-C11 cycloalkyloxy,
C6-C10 aryloxy,
C7-C11 arylalkyloxy,
C2-C10 alkylcarbonyloxyalkyloxy,
C2-C10 alkoxycarbonyloxyalkyloxy,
C2-C10 alkoxycarbonylalkyloxy,
C4-C10 cycloalkylcarbonyloxyalkyloxy,
C4-C10 cycloalkoxycarbonyloxyalkyloxy,
C4-C10 cycloalkoxycarbonylalkyloxy,
C7-C11 aryloxycarbonylalkyloxy,
C7-C12 aryloxycarbonyloxyalkyloxy,
C7-C12 arylcarbonyloxyalkyloxy,
C4-C10 alkoxyalkylcarbonyloxyalkyloxy,
(5-(C1-C4 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R28) (R29) Nxe2x80x94(C1-C10 alkoxy)-; p2 Wa is selected from:
H,
hydroxy,
xe2x80x94NR16R20,
xe2x80x94NR25R26,
C1-C10 alkoxy,
C1-C10 alkyl substituted with 0-3 R8, and
aryl substituted with 0-3 R8,
Wb is selected from:
H,
CH2OH,
CH2OR12,
CH2CO2R12,
CH2C(xe2x95x90O)NHR18,
CH2NR16R20,
CH2NR25R26,
C1-C8 alkyl substituted with 0-2 R8,
C3-C6 alkenyl,
C3-C10 cycloalkyl,
C4-C11 cycloalkylmethyl,
heteroaryl,
heteroaryl(C1-C6 alkyl),
aryl substituted with 0-3 R8, and
aryl(C1-C6 alkyl), said aryl substituted with 0-3 R8;
R5 and R6 are taken together to be Cxe2x95x90O;
R7 is H or C1-C4 alkyl substituted with 0-3 R8;
R7a and R7b are independently selected from H, methyl, and ethyl;
alternatively, when R7 and R7a occur on adjacent carbons R7 and R7a may be taken together to form a carbon-carbon double bond;
alternatively, when R7a and R7b occur on adjacent carbons R7a and R7b may be taken together to form a six carbon aromatic ring;
R8 is selected from:
H, hydroxy, cyano, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)R13, xe2x80x94OC(xe2x95x90O)R13, xe2x80x94OC(xe2x95x90O)OR14, xe2x80x94OR12, xe2x80x94OCH2CO2R12, xe2x80x94CO2CH2CO2R12, xe2x80x94OC(xe2x95x90O)NR23R24, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR25R26, xe2x80x94NR27C(xe2x95x90O)R13, xe2x80x94NR27C(xe2x95x90O)OR14, xe2x80x94NR27SO2R14, xe2x80x94SR14, xe2x80x94SOR14, xe2x80x94SO2R14, xe2x80x94SO2NR23R24, C1-C10 alkoxy, C1-C10 alkylcarbonyl, C2-C6 alkenyl, C3-C10 cycloalkyl, C4-C11 cycloalkylmethyl,
aryl, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, CO2R12, SO2Me, SOMe, SMe, or xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2;
R9 is selected from H, halogen, CF3, CN, C1-C4 alkyl, or C1-C4 alkoxy;
R10 is selected from:
H, hydroxy, CN, carboxy, xe2x80x94NR25R26; C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C7-C14 bicycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, aryl, piperidinyl, morpholinyl, and pyridinyl;
R11 is selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
R12 is selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
R13 is selected from:
hydrogen, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
R14 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
R15 is selected from:
H, OH, xe2x80x94OR12, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94OC(xe2x95x90O)NR23R24, C1-C10 alkoxycarbonyl substituted with 0-2 R8;
C1-C10 alkyl substituted with 0-3 R8;
C2-C10 alkenyl substituted with 0-3 R8; and
C1-C10 alkoxy substituted with 0-3 R8;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR17, xe2x80x94C(xe2x95x90O)R18, xe2x80x94C(xe2x95x90O)NR17R18, xe2x80x94C(xe2x95x90O)NHSO2R17, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R17, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR17, xe2x80x94C(xe2x95x90O)NHSO2NHR17, xe2x80x94SO2R17, xe2x80x94SO2NR17R18, and xe2x80x94SO2NHC(xe2x95x90O)OR17;
R17 is selected from:
C1-C8 alkyl substituted with 0-2 R19,
C3-C8 alkenyl substituted with 0-2 R19,
C3-C8 alkynyl substituted with 0-2 R19,
C3-C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1-C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19;
R18 is selected from H or R17;
R19 is selected from:
H, halogen, CF3, CN, NO2, NR25R26, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C3-C11 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C1-C4 alkoxycarbonyl;
R20 is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C3-C11 cycloalkyl(C1-C4 alkyl)-, aryl, and aryl(C1-C10 alkyl)-;
R21 and R22 are each independently H, methyl, ethyl, propyl, or butyl;
R23 is selected from:
hydrogen, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, hydroxy, C1-C6 alkoxy, benzyloxy, aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, adamantylmethyl, and C1-C10 alkyl substituted with 1-2 R10;
R24 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
R25 and R26 are, independently, selected from:
H, C1-C10 alkyl, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C4 alkyl)-, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, aryl(C1-C10 alkoxy)carbonyl, aryl(C1-C10 alkyl)sulfonyl, aryl(C2-C10 alkenyl)sulfonyl, C2-C6 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C4 alkyl)-, C3-C10 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroaryl(C1-C4 alkyl)carbonyl,
wherein said aryl groups are optionally substituted with 1-3 substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2;
R27 is selected from H, methyl, ethyl, propyl, butyl, benzyl, phenethyl, cyclopropyl, and cyclopropylmethyl;
R28 and R29 are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
n is 0 or 1;
q is 1, 2, 3, or 4;
r is 0, 1, or 2; and
s is 1, 2, 3, or 4.
[9] Preferred compounds of this second embodiment are those compounds of Formula (I) wherein:
R1 is selected from
R2a(R3)Nxe2x80x94Vxe2x80x94, R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94, R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94, R2(R11O)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94, R2(R2b)N(R11ONxe2x95x90)Cxe2x80x94Vxe2x80x94, 
V is selected from:
xe2x80x94(C1-C4 alkyl)-,
xe2x80x94(phenyl)-, said phenyl substituted with 0-2 groups independently selected from R9,
xe2x80x94(pyridyl)-, said pyridyl substituted with 0-2 groups independently selected from R9, or
xe2x80x94(pyridazinyl)-, said pyridazinyl substituted with 0-2 groups independently selected from R9;
Z is selected from: a bond, O, and S(xe2x95x90O)2;
X is xe2x80x94OCH2CH(Wa)xe2x80x94, xe2x80x94SCH2CH(Wa)xe2x80x94, xe2x80x94NHCH2CH(Wa)xe2x80x94, xe2x80x94OCH(Wb)xe2x80x94, xe2x80x94SCH(Wb)xe2x80x94, or xe2x80x94NHCH(Wb)xe2x80x94;
Wa is selected from:
H, hydroxy, xe2x80x94NHR16, xe2x80x94NR25R26, C1-C10 alkoxy, C1-C10 alkyl substituted with 0-3 R8, and aryl substituted with 0-3 R8,
R7 is selected from:
H, CH2OH, CH2OR12, CH2CO2R12, CH2C(xe2x95x90O)NHR24, CH2NR25R26, and C1-C4 alkyl substituted with 0-1 R8;
R12 is selected from H, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
R15 is selected from: H, OH, xe2x80x94OR12, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)NR23R24, and xe2x80x94OC(xe2x95x90O)NR23R24;
R16 is selected from: xe2x80x94C(xe2x95x90O)OR17, xe2x80x94C(xe2x95x90O)R18, xe2x80x94SO2R17, and xe2x80x94SO2NR17R18;
R17 is selected from:
C1-C8 alkyl substituted with 0-2 R19,
C3-C8 alkenyl substituted with 0-2 R19,
C3-C8 alkynyl substituted with 0-2 R19,
C3-C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1-C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, said heterocyclic ring being substituted with 0-4 R19, said heterocyclic ring being substituted with 0-4 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring being substituted with 0-4 R19;
R18 is selected from H or C1-C5 alkyl;
n is 0 or 1;
q is 1, 2, 3, or 4;
r is 0, 1, or 2; and
s is 1, 2, 3, or 4.
[10] More preferred compounds of this second embodiment are those compounds of Formula (Ia) 
wherein:
R1 is selected from
R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94, R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94, 
V is selected from:
xe2x80x94(C1-C4 alkyl)-,
xe2x80x94(pyridyl)-, and
xe2x80x94(phenyl)-, said phenyl substituted with 0-2 groups independently selected from F, Br, methyl, and methoxy;
Z is a bond or O;
R2, R2b, and R3 are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C4 alkyl)-, C2-C7 alkylcarbonyl, C1-C4 haloalkyl, aryl, arylcarbonyl, aryl(C1-C4 alkyl)-, benzhydryl, benzhydryl (C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, and
a cleavable protecting group selected from:
C1-C6 alkoxycarbonyl,
C3-C8 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl,
aryloxycarbonyl,
aryl(C1-C8 alkoxy)carbonyl,
(C1-C6 alkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
(C3-C8 cycloalkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
wherein at least one of R2, R2b, and R3 is H or a cleavable protecting group;
wherein said aryl groups of R2, R2b, and R3 may be substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, xe2x80x94CN, xe2x80x94SO2(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and
said heteroaryl groups of R2, R2b, and R3 may be substituted with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SO2CH3, and xe2x80x94NR21R22;
alternatively, R2 and R2b can be taken together with the nitrogen atom to which they are attached to form a 5-10 membered heterocyclic ring system selected from morpholine, piperidine, piperazine, pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine, 1,4-benzoxazine, 8-oxo-3-aza-bicyclo[3.2.1]octane, 1,4-dioxa-8-azaspiro[4.5]decane, or azepine, said heterocyclic ring being substituted with 0-2 R4;
X is xe2x80x94OCH2CH(Wa)xe2x80x94, xe2x80x94NHCH2CH(Wa)xe2x80x94, xe2x80x94OCH(Wb)xe2x80x94, or xe2x80x94NHCH(Wb)xe2x80x94;
Y is selected from hydroxy,
C1-C6 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
Wa is H or xe2x80x94NHR16;
Wb is H, methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, pyridylethyl, (indol-3-yl)ethyl, CH2C(xe2x95x90O)NHR18, and CH2NHR16;
R8 is selected from:
H, hydroxy, cyano, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)R13, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR25R26, xe2x80x94SR14, xe2x80x94SOR14, xe2x80x94SO2R14, C1-C10 alkoxy, C1-C10 alkylcarbonyl,
aryl, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;
R15 is selected from: H, OH, xe2x80x94OR12, and xe2x80x94OC(xe2x95x90O)NR23R24;
R16 is xe2x80x94C(xe2x95x90O)OR17 or xe2x80x94SO2R17;
R17 is selected from:
C1-C8 alkyl,
C2-C8 alkenyl,
aryl substituted with 0-4 R19,
aryl(C1-C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, said heterocyclic ring being substituted with 0-4 R19, said heterocyclic ring being substituted with 0-4 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring being substituted with 0-4 R19;
R19 is selected from:
H, halogen, CF3, CN, NO2, NR25R26, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C3-C11 cycloalkyl (C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C1-C4 alkoxycarbonyl;
n is 0 or 1;
q is 1, 2, 3, or 4;
r is 0, 1, or 2; and
s is 1, 2, 3, or 4.
[11] Even more preferred compounds of this second embodiment are compounds of Formula (Ib), wherein:
R1 is R2(R2b)N(R3Nxe2x95x90)Cxe2x80x94Vxe2x80x94 or R2(R2b)N(R3Nxe2x95x90)CNHxe2x80x94Vxe2x80x94;
V is xe2x80x94(pyridyl)- or xe2x80x94(phenyl)-, said phenyl substituted with 0-2 groups independently selected from F, Br, methyl, and methoxy;
Z is a bond or O;
R2, R2b, and R3 are independently selected from:
H, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C4 alkyl)-, C2-C7 alkylcarbonyl, C1-C4 haloalkyl, arylcarbonyl, aryl(C1-C4 alkyl)-, benzhydryl, heteroaryl, heteroaryl(C1-C4 alkyl)-, and
a cleavable protecting group selected from:
C1-C4 alkoxycarbonyl,
C3-C6 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl,
aryl(C1-C8 alkoxy)carbonyl,
(C1-C6 alkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
(C3-C8 cycloalkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
wherein at least one of R2, R2b, and R3 is H or a cleavable protecting group;
wherein said aryl groups of R2, R2b, and R3 may be substituted with 0-3 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CF3, xe2x80x94CN, xe2x80x94SO2(CH3), xe2x80x94SO2(C2H5), xe2x80x94SO2(C3H7), xe2x80x94SO2(C4H9), xe2x80x94NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and
said heteroaryl groups of R2, R2b, and R3 may be substituted with 0-2 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CF3, SO2CH3, and xe2x80x94NR21R22;
alternatively, R2 and R2b can be taken together with the nitrogen atom to which they are attached to form a 5-10 membered heterocyclic ring system selected from morpholine, piperidine, piperazine, pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine, 1,4-benzoxazine, 8-oxo-3-aza-bicyclo[3.2.1]octane, 1,4-dioxa-8-azaspiro[4.5]decane, or azepine, said heterocyclic ring being substituted with 0-2 R4;
R4, when a substituent on carbon, is independently selected from H, methyl, ethyl, propyl, butyl, and phenyl; wherein said phenyl groups may be optionally substituted with 0-3 groups selected from hydroxy, halogen, methoxy, methyl, ethyl, CF3, SCH3, xe2x80x94NH2, xe2x80x94NH(CH3), xe2x80x94N(CH3)2, methylenedioxydiyl, and ethylenedioxydiyl;
alternatively, when two R4 groups are attached to adjacent carbon atoms, they may be taken together with the atoms to which they are attached to form a fused 5-7 membered saturated, unsaturated or aromatic carbocyclic ring;
alternatively, when R4 is attached to a saturated carbon atom, it may also be xe2x95x90O or xe2x95x90S;
R4 when a substituent on nitrogen, is independently selected from H, methyl, ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, phenyl, phenylmethyl, phenylethyl, pyridyl, pyridylmethyl wherein said phenyl or pyridyl groups may be additionally substitututed with 0-2 groups selected from hydroxy, halogen, methoxy, methyl, ethyl, CF3, SCH3, xe2x80x94NH2, xe2x80x94NH(CH3), and xe2x80x94N(CH3)2;
R4 when a substituent on sulfur, may be xe2x95x90O;
X is xe2x80x94OCH2CH(Wa)xe2x80x94 or xe2x80x94OCH(Wb)xe2x80x94;
Y is selected from hydroxy; methoxy; ethoxy; isopropoxy; n-butyloxy; isobutyloxy; t-butoxy; benzyloxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
Wa is H or xe2x80x94NHR16;
Wb is H, methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, pyridylethyl, (indol-3-yl)ethyl, CH2C(xe2x95x90O)NHR18, and CH2NHR16;
R8 is selected from:
H, hydroxy, cyano, xe2x80x94CO2R12, xe2x80x94C(xe2x95x90O)R13, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR25R26, xe2x80x94SR14, xe2x80x94SOR14, xe2x80x94SO2R14, C1-C4 alkoxy, C1-C4 alkylcarbonyl,
aryl, wherein said aryl is substituted with 0-3 groups selected from halogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl, CF3, CO2R12, SO2Me, SOMe, SMe or xe2x80x94NMe2,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;
R15 is H;
R16 is xe2x80x94SO2R17, xe2x80x94C(xe2x95x90O)OCH2CH2CH2CH3, xe2x80x94C(xe2x95x90O)OCH2CH(CH3)2 or xe2x80x94C(xe2x95x90O)OCH2(C6H5);
R17 is selected from:
C1-C8 alkyl,
aryl substituted with 0-2 R19,
aryl(C1-C6 alkyl)-substituted with 0-2 R19,
a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, said heterocyclic ring being substituted with 0-2 R19, said heterocyclic ring being substituted with 0-2 R19, and
C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring being substituted with 0-2 R19;
R19 is selected from:
H, halogen, CF3, CN, NO2, NR25R26, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C4 alkyl)-, C1-C4 alkoxy, and C1-C4 alkoxycarbonyl;
n is 1; and
s is 1 or 2.
[12] Specifically preferred compounds of this second embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
[1-[[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(phenylmethylamino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(n-propylamino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(ethylamino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(piperidino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(thiazolidino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(4-phenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(pyrrolidino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(2,6-dimethylpiperazino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(2-fluorophenyl)piperazino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(2-methylphenyl)piperazino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(thiomorpholino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid; and
[1-[[3-[4-[(4-propylpiperazino)iminomethyl]phenyl]-isoxazolin-5-yl]carbonyl]piperidin-4-yl]oxyacetic acid;
[1-[[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-yl]carbonyl]-4-piperidinyl]acetic acid; and
[1-[[3-[4-[(1,2,3,4-tetrahydro-2,7-naphthyridino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]-4-piperidinyl]-acetic acid.
In another preferred embodiment, the present invention provides a compound of Formula (I) or (Ia) wherein the stereochemistry of the isozazolin-5-yl-CR5R6-moiety is either isozazolin-5(S)-yl-CR5R6xe2x80x94 or isozazolin-5(R)-yl-CR5R6xe2x80x94. Depending on the substitution pattern of the isoxazoline, a compound of Formula (I) or (Ia) with a isozazolin-5(S)-yl-CR5R6xe2x80x94 or isozazolin-5(R)-yl-CR5R6-moiety is depicted by one of the following formulas: 
In the present invention it has been discovered that the compounds of Formula (I) above are useful as inhibitors of cell-matrix and cell-cell adhesion processes. The present invention includes novel compounds of Formula (I) and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the extracellular matrix which comprises administering to a host in need of such treatment a therapeutically effective amount of such compound of Formula I.
In the present invention it has also been discovered that the compounds of Formula (I) above are useful as inhibitors of glycoprotein IIb/IIIa (GPIIb/IIIa) The compounds of the present invention inhibit the activation and aggregation of platelets induced by all known endogenous platelet agonists.
The present invention also provides pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
The compounds of Formula (I) of the present invention are useful for the treatment (including prevention) of thromboembolic disorders. The term xe2x80x9cthromboembolic disordersxe2x80x9d as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (I) described above.
The compounds of Formula (I) of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, infammation, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, tumors, metastasis, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases. The compounds of Formula (I) of the present invention may also be useful for wound healing.
The compounds of the present invention are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal. The compounds of the invention may be used as a medicament for blocking fibrinogen from acting at its receptor site in a mammal.
Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption, and where the aggregated platelets may form thrombi and thromboemboli. The compounds of the present invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Extracorporeal circulation is routinely used during cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the extracorporeal circuit. Platelets released from artificial surfaces show impaired homeostatic function. The compounds of the invention may be administered to prevent such ex vivo adhesion.
The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
Other applications of these compounds include prevention of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures. The compounds of the present invention may also be used to prevent myocardial infarction. The compounds of the present invention are useful as thrombolytics for the treatment of thromboembolic disorders.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents select from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, streptokinase, or reteplase.
The compounds of Formula (I) of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.
The term xe2x80x9cintegrinxe2x80x9d as used herein refers to any of the many cell surface receptor proteins, also referred to as adhesion protein receptors, which have been identified which bind to extracellular matrix ligands or other cell adhesion protein ligands thereby mediating cell-cell and cell-matrix adhesion processes. The integrins are encoded by genes belonging to a gene superfamily and are typically composed of heterodimeric transmembrane glycoproteins containing xcex1- and xcex2-subunits. Integrin subfamilies contain a common xcex2-subunit combined with different xcex1-subunits to form adhesion protein receptors with different specificities.
The integrin glycoprotein IIb/IIIa (referred to herein as GPIIb/IIIa or IIb/IIIa or the fibrinogen receptor) is the membrane protein mediating platelet aggregation. GPIIb/IIIa in activated platelets is known to bind four soluble RGD-containing adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. In addition to GPIIb/IIIa, a number of other integrin cell surface receptors have been identified, for example, xcex1vxcex23 and xcex15xcex21.
The term xe2x80x9cintegrin antagonistsxe2x80x9d as referred to herein (also referred to herein as integrin inhibitors) includes compounds (including peptidomimetic compounds and other small molecule compounds) which act as inhibitors of the binding of the integrin protein to endogenous protein ligands of such integrin. Preferred integrin inhibitors used in the present invention are RGD-peptidomimetic compounds. As used herein, the term xe2x80x9cRGD-peptidomimetic compoundsxe2x80x9d refers to chemical compounds which bind to the RGD-binding region of the integrin and which block RGD-mediated binding of one or more adhesive proteins to such integrin. Preferred in the present invention are antagonists of the xcex1vxcex23 and GPIIb/IIIa integrin.
By xe2x80x9ctherapeutically effective amountxe2x80x9d it is meant an amount of a compound of Formula (I) that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease. Such disease conditions or diseases include thromboembolic disorders and cell adhesion prosesses as disclosed herein.
By xe2x80x9cadministered in combinationxe2x80x9d or xe2x80x9ccombination therapyxe2x80x9d it is meant that the compound of Formula (I) and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
The term xe2x80x9canti-coagulant agentsxe2x80x9d (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as Coumadin(trademark)), heparin, and low molecular weight heparin.
The term xe2x80x9canti-platelet agentsxe2x80x9d (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Piroxicam is commercially available from Pfizer Inc. (New York, N.Y.), as Feldane(trademark). Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include other IIb/IIIa antagonists, such as ReoPro(trademark) (abciximab, available from Centocor), Integrilin(trademark) (eptifibatide, available from COR Therapeutics), and Aggrastat(trademark) (tirofiban, available from Merck and Co.).
Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
The phrase xe2x80x9cthrombin inhibitorsxe2x80x9d (or xe2x80x9canti-thrombin agentsxe2x80x9d), as used herein, denotes inhibitors of the serine protease thrombin and other inhibitors of thrombin synthesis such as factor Xa inhibitors. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
The term xe2x80x9cfactor Xa inhibitorxe2x80x9d, as used herein, denotes inhibitors of factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin. The generation of thrombin from its precursor prothrombin is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Therefore, it is envisioned that adminstration of an inhibitor of thrombin synthesis, such as a factor Xa inhibitor, in combination therapy with a IIbIIIa inhibitor of the instant invention may be an additional method in treating cardiovascular disease, thrombosis, reocclusion following thrombolysis, reperfusion injury, or restenosisother than administering a compound of Formula (I) alone. Such factor Xa inhibitors include, but are not limited to, DX-9065a (Daiichi), ORG31540 (Organon), SANORG 32701 (Sanofi/Organon), and BX-807834 (Berlex). Such factor Xa inhibitors also include, but are not limited to, compounds disclosed in WO97/23212, published Jul. 3, 1997; WO97/38984, published Oct. 23, 1997; WO97/30971, published Aug. 28, 1997; WO98/01428, published Jan. 15, 1998; WO98/06694, published Feb. 19, 1998; WO98/28269, published Jul. 2, 1998; and WO98/28282, published Jul. 2, 1998; each reference herein incorporated by reference in its entirety.
The phrase xe2x80x9cthrombolytic agentsxe2x80x9d or xe2x80x9cfibrinolytic agentsxe2x80x9d (or xe2x80x9cthrombolyticsxe2x80x9d or xe2x80x9cfibrinolyticsxe2x80x9d), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase, streptokinase, or reteplase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. Anistreplase is commercially available as Eminase(trademark). The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase. Reteplase is manufactured by Boehringer Mannheim Corp. and commercially available as Retavase(trademark).
Administration of the compounds of Formula (I) of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of fibrinogen to platelet GPIIb/IIIa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving GPIIb/IIIa. The compounds of the present invention may also be used in diagnostic assays involving platelet GPIIb/IIIa.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example but not limited to, R2, R2b, R8, R9, R10, R11, R12, R13, R14, R19, R21, R22, R23, R24, R25, R26, and s, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R8, then said group may optionally be substituted with up to two R8 and R8 at each occurrence is selected independently from the defined list of possible R8.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula I, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperidinyl, morpholinyl, or pyridinyl, unless specified otherwise, said piperidinyl, morpholinyl, or pyridinyl group may be bonded to the rest of the compound of Formula (I) via any atom in such piperidinyl, morpholinyl, or pyridinyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration, having the specified number of carbon atoms, and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, 1-butenyl, 2-butenyl and the like. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration, having the specified number of carbon atoms, and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.
The term xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted independently with 1 or more halogens (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)), such as, but not limited to, xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94CF2Br, xe2x80x94CH2CF3, xe2x80x94CF2CF3, xe2x80x94CH(CF3)2 and the like.
As used herein, xe2x80x9calkyloxyxe2x80x9d or xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, for example methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, s-butoxy and t-butoxy. The term xe2x80x9caryloxyxe2x80x9d is intended to mean phenyl or naphthyl attached through an oxygen bridge;
The term xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups having the specified number of carbon atoms, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl (c-Pr), cyclobutyl (c-Bu), cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, [3.3.0]bicyclooctyl, [2.2.2]bicyclooctyl, adamantyl and so forth. More specifically, xe2x80x9cbicycloalkylxe2x80x9d is intended to include saturated bicyclic ring groups having the specified number of carbon atoms, such as [3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl (decalin), [2.2.2]bicyclooctyl, and so forth.
Additionally, the terms xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, may alternatively and equivalently be denoted herein as xe2x80x9cxe2x80x94(alkyl)xe2x80x94xe2x80x9d, xe2x80x9cxe2x80x94(alkenyl)xe2x80x94xe2x80x9d and xe2x80x9cxe2x80x94(phenyl)xe2x80x94xe2x80x9d, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean 6 to 10 membered monocyclic or bicyclic unsaturated carbon ring, for example phenyl or naphthyl. As used herein xe2x80x9carylxe2x80x9d is optionally substituted with 0-3 groups independently selected from methyl, methoxy, amino, hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, C1-C4 haloalkyl, methylenedioxydiyl, or ethylenedioxydiyl.
The term xe2x80x9carylalkylxe2x80x9d represents an aryl group attached through an alkyl bridge having the specified number of carbon atoms.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, lH-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, 1,4-benzoxazine, and 8-oxa-3-azabicyclo[3.2.1]octane. Preferred heterocyclic rings are pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
As used herein, the term xe2x80x9cchiral aminexe2x80x9d refers to any amine containing compound that also contains a chiral center. Such compounds include, by way of example and without limitation, either enantiomer of cinchonidine, ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.
As used herein, xe2x80x9ccarbonylxe2x80x9d means a carbon double bonded to oxygen and additionally substituted with two groups through single bonds; xe2x80x9ccarbonyloxyxe2x80x9d means a carbon double bonded to oxygen and additionally bonded through a single bonds to two groups, one of which is an oxygen. As used herein, xe2x80x9csulfonylxe2x80x9d is intended to mean a sulfur bonded through double bonds to two oxygens and bonded to two additional groups through single bonds.
As used herein, any carbon range such as xe2x80x9cCx-Cyxe2x80x9d is intended to mean a minimum of xe2x80x9cxxe2x80x9d carbons and a maximum of xe2x80x9cyxe2x80x9d carbons representing the total number of carbons in the substituent to which it modifies, for example C1-C6 alkyl or C3-C10 cycloalkyl(C1-C6 alkyl)- or aryl(C1-C6 alkyl) or aryl(C1-C6 alkyl)carbonyl means an alkyl substituent of one to six carbons independent of the cycloalkyl, aryl or carbonyl respectively. However, if not specified, for example in xe2x80x9cC2-C10 alkylcarbonyloxyalkyloxyxe2x80x9d or xe2x80x9cC4-C10 cycloalkylcarbonyloxyalkyloxyxe2x80x9d or xe2x80x9cC7-C11 aryloxycarbonylalkyloxyxe2x80x9d, the carbon range xe2x80x9cCx-Cyxe2x80x9d is intended to mean the range of total number of carbons in the substituent not including the xe2x80x9ccarbonylxe2x80x9d.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound of Formula (I) is modified by making acid or base salts of the compound of Formula I. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be manufactured or therapeutically delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula (I) wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. An example any group that, when administered to a mammalian subject, cleaves to form a free amino, is disclosed in the definition of R2, R2b, or R3, as xe2x80x9ca cleavable protecting group.xe2x80x9d Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like. Examples of representative amino and carboxyl prodrugs are included under the definitions of R2, R2b, R3, and Y.
The pharmaceutically acceptable salts of the compounds of Formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula (I) formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula (I) which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of Formula (I) with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
Compounds of Formula (I) can be conveniently prepared by dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles (for reviews of 1,3-dipolar cycloaddtiion chemistry, see 1,3-Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, N.Y., 1984; Kanemasa and Tsuge, Heterocycles 1990, 30, 719). The requisite nitrile oxides are in turn prepared from commercially available precursors or appropriately substituted aldehydes via the intermediate oxime.
Scheme 1 illustrates one synthetic sequence which will provide compounds of Formula (I) of this invention. 
Treatment of commercially available allyl bromide with 4-cyanobenzaldehyde chlorooxime in a suitable solvent, such as tetrahydrofuran or dichloromethane in the presence of a mild base, such as sodium bicarbonate or triethylamine, affords the isoxazoline intermediate, 1(a). Coupling of 1(a) with precursor 1(b) was carried out with triethylamine or sodium hydride and dimethyl formamide as a solvent to give compound 1(c) (for review of this type of reaction, see The Chemistry of the Amino Group (Patai, ed.), Wiley, N.Y., 1968; The Acyclic Aliphatic Tertially Amines (Spialter and Pappalardo), Macmillan, N.Y., 1965). A Pinner synthesis was performed on intermediate 1(c) to yield 1(d). Further treatment of 1(d) with different appropriate amines provides 1(f). Finally, deprotection of compound 1(f) was carried out using standard methods of removal of carboxy protecting group to provide target compounds of formula 1(g). 
Compounds of Formula (I), wherein X is 2(a) can also be prepared from cycloaddition product 1(a) as depicted in Scheme 2. In a similar manner as described earlier, coupling of 1(a) and 2(a) can be achieved upon heating with a suitable base such as cesium carbonate or triethylamine in dimethyl formamide. Treatment of compound 2(b) with gaseous hydrogen chloride, followed by the addition of several different amines affords 2(d). Subsequent removal of carboxy protecting group using standard methods gives compounds of formula 2(e).
The preparations of compounds 1(b) and 2(a) are shown in Scheme 3 and 4. For intermediate 1(b) (Scheme 3), reduction of 4-pyridylacetic acid hydrochloride with 5% rhodium catalyst gives the corresponding piperidyl derivative. Further treatment of 4-piperidylacetic acid hydrochloride with thionyl chloride in the presence of methanol yields the desired compound 1(b). Intermediate 2(a) (Scheme 4) can be obtained following a three-step procedure. Either 3-pyrrolidinol or 4-piperidinol can be treated with benzyl chlorofomate to give the corresponding amine protected derivatives. Subsequent treatment with tert-butyl bromoacetate and hydrogenation provides compounds of formula 2(a). 
Additional isoxazoline compounds useful in the present invention can be prepared as outlined in Scheme 5 wherein 1,3-dipolar cycloaddition is carried out using commercially available methyl acrylate as a dipolarophile. Treatment of methyl acrylate with 4-cyanobenzaldehyde chlorooxime in a suitable solvent such as tetrahydrofuran or dichloromethane, in the presence of a mild base, such as sodium bicarbonate or triethylamine, provides isoxazoline intermediate 10(a). Subsequent hydrolysis of the methyl ester using conventional methods known to one skilled in the art of organic synthesis gives the corresponding acid 10(b). Coupling of compound 10(b) to either intermediate 1(b) or 2(a) (see Scheme 3) affords 10(c).
The coupling is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of the acid to the corresponding procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic amido ester) method, carbonyldiimidazole method, or coupling with phosphorus reagents such as BOP reagent. Some of these methods (especially the carbodiimide) can be enhanced by addition of 1-hydroxybenzotriazole. Compound 10(c) was treated with gaseous hydrogen chloride in an appropriate solvent such as ethanol to yield 10(d). Further treatment of compound 10(d) with an appropriate amine in a suitable solvent such as pyridine or methanol provides 10(e). Deprotection of compound 10(e) is carried out using standard methods of removal of carboxy protecting group to give target compounds of formula 10(f). 
The detailed processes for preparing the compounds of Formula (I) are illustrated by the following examples. It is, however, understood that this invention is not limited to the specific details of these examples. Melting points (mp) are uncorrected. Proton nuclear magnetic resonance spectra (NMR) were measured in chloroform-d (CDCl3) unless otherwise specified and the peaks are reported in parts per million (ppm) downfield from tetramethylsilane (TMS). the coupling patterns are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet; bm, broad multiplet. Infrared spectra are reported in reciprocal centimeters (cmxe2x88x921). All final compounds gave satisfactory nmr and HRMS data an d were anlayzed to be  greater than 98% pure by reverse ph ase analytical HPLC.